Perivascular adipose tissue (PVAT) surrounds (coronary) arteries and may be involved in local stimulation of atherosclerotic plaque formation. PVAT can be quantified using a number of techniques, including for example, echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI). The quantity of PVAT correlates with some parameters of metabolic syndrome including increased waist circumference, hypertriglyceridemia and hyperglycemia, and with coronary atherosclerosis. PVAT has long been known to secrete pro-inflammatory proteins and induce inflammation of the artery wall. The long-held understanding of the pathology of atherogenesis in the vascular wall was that it is stimulated externally, and it was suggested that PVAT played a key role in this process.
Atherosclerosis is a progressive process in which an artery wall thickens as a result of invasion and accumulation of white blood cells. This inflammatory process results in plaques within the vessel wall containing living white blood cells, dead cell debris and fatty deposits including cholesterol and triglycerides.
Stable atherosclerotic plaques, which tend to be asymptomatic, are typically rich in extracellular matrix and smooth muscle cells, while unstable plaques are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap eventually induce clot formation in the lumen, and such clots can block arteries or detach, move into the circulation and eventually block smaller downstream vessels causing thromboembolism. Chronically expanding plaques are frequently asymptomatic until vessel occlusion (stenosis) is severe enough that blood supply to downstream tissue is insufficient.
Atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations and blood flow is not immediately affected. Indeed, plaque ruptures are also asymptomatic unless they result in sufficient narrowing or closure of an artery that impedes blood flow to different organs so as to induce symptoms. Typically, the disease is only diagnosed when the patient experiences other cardiovascular disorders such as stroke or heart attack. Symptomatic atherosclerosis is typically associated with men in their 40s and women in their 50s to 60s. Sub-clinically, the disease begins to appear in childhood, and noticeable signs can begin developing at puberty. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes.
Atherosclerosis may cause narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, and this can produce symptoms such as the chest pain of angina, shortness of breath, sweating, nausea, dizziness or light-headedness, breathlessness or palpitations. Cardiac arrhythmias may also result from cardiac ischemia. Atherosclerosis that causes narrowing in the carotid arteries, which supply blood to the brain and neck, can produce symptoms such as a feeling of weakness, not being able to think straight, difficulty speaking, becoming dizzy and difficulty in walking or standing up straight, blurred vision, numbness of the face, arms, and legs, severe headache and losing consciousness. These symptoms may also be present in stroke, which is caused by marked narrowing or closure of arteries going to the brain leading to brain ischemia and death of cells in the brain. Peripheral arteries, which supply blood to the legs, arms, and pelvis may also be affected. Symptoms can include numbness within the affected limbs, as well as pain. Plaque formation may also occur in the renal arteries, which supply blood to the kidneys. Plaque occurrence and accumulation leads to decreased kidney blood flow and chronic kidney disease, which, like all other areas, are typically asymptomatic until late stages.
Inflammation is pivotal in atherogenesis (Ross R (1999). Atherosclerosis—an inflammatory disease. N Engl J Med 340(2):115-26; and Major A S, and Harrison D G (2011). What fans the fire: insights into mechanisms of inflammation in atherosclerosis and diabetes mellitus. Circulation 124(25):2809-11) and modalities that can accurately detect vascular inflammation at an early stage would enable better cardiovascular risk stratification and implementation of appropriate therapeutic interventions. Current tools to assess vascular inflammation that rely on systemic plasma biomarkers (e.g. C-reactive protein, pro-inflammatory cytokines) are not directly related to the process of atherogenesis (Weintraub W S, and Harrison D G (2000). C-reactive protein, inflammation and atherosclerosis: do we really understand it yet? Eur Heart J 21(12):958-60), and provide very poor associations with local vascular biological processes (Lee R, Margaritis M, Channon K M, and Antoniades C (2012). Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations. Current medicinal chemistry 19(16):2504-20; and Margaritis M, Antonopoulos A S, Digby J, Lee R, Reilly S, Coutinho P, Shirodaria C, Sayeed R, Petrou M, De Silva R, et al (2013). Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation 127(22):2209-21). Moreover, existing imaging tools (invasive such as intravascular ultrasound/optical coherence tomography or non-invasive such as Computerized Tomography (CT) Angiography/fluorodeoxyglucose(18F)-positron emission tomography) are unable to provide reliable information on vascular inflammation in human coronary arteries (Fifer K M, Qadir S, Subramanian S, Vijayakumar J, Figueroa A L, Truong Q A, Hoffmann U, Brady T J, and Tawakol A (2011). Positron emission tomography measurement of periodontal 18F-fluorodeoxyglucose uptake is associated with histologically determined carotid plaque inflammation. Journal of the American College of Cardiology 57(8):971-6). Coronary calcium scoring (CCS) is the only non-invasive imaging biomarker with predictive value in primary prevention (Greenland P, LaBree L, Azen S P, Doherty T M, and Detrano R C (2004). Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. Jama 291(2):210-5), but it describes non-reversible structural changes of the vascular wall, and it is not altered by interventions that reduce cardiovascular risk (e.g. statins) (Alexopoulos N, Melek B H, Arepalli C D, Hartlage G R, Chen Z, Kim S, Stillman A E, and Raggi P (2013). Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning). Journal of the American College of Cardiology 61(19): 1956-61). A novel imaging biomarker that could overcome these limitations and non-invasively detect vascular inflammation would be invaluable in clinical research and risk stratification of coronary artery disease (Hoefer I F, Steffens S, Ala-Korpela M, Back M, Badimon L, Bochaton-Piallat M L, Boulanger C M, Caligiuri G, Dimmeler S, Egido J, et al (2015). Novel methodologies for biomarker discovery in atherosclerosis. Eur Heart J 2015 Jun. 5. pii: ehv236[Epub ahead of print]).
It has recently become clear that vascular inflammation and oxidative stress has the ability to affect the biology of PVAT as the vascular wall releases mediators able to exert a paracrine effect on the neighbouring PVAT (see e.g. Margaritis et al. Circulation 2013; 127(22):2209-21). This observation was in contrast to the classical theory according to which PVAT sends paracrine signals to the vascular wall. It is now understood that the biology of PVAT is shaped by signals received from the blood vessel it surrounds, and characterisation of that PVAT can provide useful information regarding the biology and health of that blood vessel.
Adipose tissue releases a wide range of bioactive molecules that exert endocrine and paracrine effects on the vascular wall (Antoniades C, Antonopoulos A S, Tousoulis D, and Stefanadis C (2009). Adiponectin: from obesity to cardiovascular disease. Obesity reviews: an official journal of the International Association for the Study of Obesity 10(3):269-79), but we have recently suggested that the communication between adipose tissue and the vascular wall is bi-directional (Margaritis M, Antonopoulos A S, Digby J, Lee R, Reilly S, Coutinho P, Shirodaria C, Sayeed R, Petrou M, De Silva R, et al (2013). Circulation 127(22):2209-21; and Antonopoulos A S, Margaritis M, Coutinho P, Shirodaria C, Psarros C, Herdman L, Sanna F, De Silva R, Petrou M, Sayeed R, et al (2015). Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes 64(6):2207-19). The biological properties of adipose tissue are largely driven by the degree of differentiation of small, immature pre-adipocytes to large, well-differentiated adipocytes, rich in intracellular lipid droplets (Ntambi J M, and Young-Cheul K (2000). Adipocyte differentiation and gene expression. The Journal of nutrition 130(12):3122S-6S). This differentiation of pre-adipocytes is orchestrated by PPAR-γ activation, a transcription factor supressed by exogenous inflammation (Bassols J, Ortega F J, Moreno-Navarrete J M, Peral B, Ricart W, and Fernandez-Real J M (2009). Study of the proinflammatory role of human differentiated omental adipocytes. Journal of cellular biochemistry 107(6):1107-17). There is no established non-invasive method to monitor adipocyte size in human adipose tissue.
Previous efforts to analyse the quantity of human adipose tissue depots by computed tomography have produced only limited data on the assessment of PVAT quality by imaging. One such attempt to assess the “quality” of pericoronary adipose tissue has been reported (Konishi et al. Atherosclerosis 2011). In that study “adipose tissue density” was quantified in arbitrarily selected 10 mm2 areas in 2D CT images, and a pericoronary CT gradient (PDG) was defined using radiodensity values determined for PVAT, arbitrarily defined as falling within 5 mm of the wall of the coronary artery, non-perivascular adipose tissue (non-PVAT), arbitrarily defined as falling more than 10 mm from the wall of the coronary artery. This approach remains a quantitative one that is prone to subjective bias, relying as it does on the judgment of the individual analysing the CT image data to select appropriate regions for analysis.
Despite the high incidence and asymptomatic nature of much vascular disease, there remains an urgent need for a tool that permits objective, non-invasive characterisation of PVAT. Available techniques provide information about the quantity of PVAT surrounding a blood vessel, but this data does not characterise the measured PVAT and it cannot discriminate between pathologies. Therefore, there is a requirement for a specific and sensitive tool to accurately characterize PVAT around a blood vessel.